Parkinson's disease (PD) is a movement disorder characterized by a progressive and selective loss of dopamine (DA) neurons in the substantia nigra. At the present, PD affects nearly one million people in the US alone and the incidence is expected to increase with an aging population. The vast majority of PD is idiopathic, occurs late in life, and does not appear to be directly related to gene mutations identified in several familial clusters of early-onset PD. Accumulating evidence indicates that environmental agents including heavy metals and infectious agents represent risk factors for idiopathic PD. The DA neurotoxicity of the heavy metal manganese has been documented and activation of brain immune cells (microglia and astroglia) by bacterial endotoxin lipopolysaccharide (LPS) is known to releases neurotoxic factors to induce neurodegeneration. However, the etiology of PD may be multi-factorial: the development of PD may be a final outcome of chronic exposure to low concentrations of multiple environmental agents. Therefore, this proposal plans to study the combined DA neurotoxicity of low concentrations of the heavy metal manganese and LPS in a chronic primary neuron-gila culture-based model of PD. The mechanism of the combined neurotoxicity will be analyzed at both the cellular and molecular levels. At the cellular level, the relative contribution to the combined neurotoxicity of the primary brain immune cells, microglia, and astroglia will be determined. At the molecular levels, the contribution to neurodegeneration of neurotoxic factors (free radicals and cytokines) by activated gila and the mechanism of neurodegenerative process will be examined. The results of these studies will enable us to gain understanding of the impact of heavy metals and microbial toxins on the DA system. These studies will also be an important component of our long-term goal of understanding the interaction between environmental factors and the nervous system in relation to the etiology of PD and finding effective strategies for the prevention and/or treatment of the disease.